We have an established program of research on genetic susceptibility in relation to disease risk. We have focused on DNA repair gene polymorphisms as we try to understand the risks and phenotypic consequences of the DNA repair gene polymorphisms that are being discovered by the NIEHS Environmental Genome Project. The large number of DNA repair genes (>200), coupled with the large number of polymorphisms (averaging >85 per gene) presents a problem given that we have little or no information about the functional consequences of the polymorphisms, and do not yet have the technology to cheaply genotype thousands of polymorphisms in case-control studies. We are taking two approaches to simplify this problem: 1) we are working to describe gene haplotypes (the specific combination of variant alleles) for DNA repair and other genes and 2) In order to find repair genotype-phenotype associations we are using single cell gel electrophoresis (the Comet assay) to measure rates of DNA repair phenotype in cells from a large sample of people where we have complete genotype information. We have started to apply our newly discovered haplotype information in our existing case-control studies. In addition, we are exploring the use of SELDI proteomic profiling as a new molecular epidemiologic tool for understanding disease susceptibility.